Safety and Efficacy of Long Term Suppression of PI3Kinase Pathway By Small Molecule PI3K-Delta Inhibitor, Leniolisib in Apds (Activated PI3Kδ Syndrome)

Abstract

Inherited gain-of-function mutations in PIK3CD encoding PI3Kδ (phosphoinositide 3-kinase delta) lead to accumulation of senescent T cells, lymphadenopathy, splenomegaly and immune-deficiency (Activated PI3Kδ Syndrome, APDS). Clinical manifestations include multilineage cytopenias and susceptibility to B cell Non-Hodgkins Lymphoma. We recently reported use of leniolisib (CDZ173), a novel, potent and selective oral PI3Kd inhibitor in six APDS patients in a 12-week, open-label, multi-center, within-subject dose-escalation study (Rao et al, Blood 23 November 2017). Leniolisib was safe and well tolerated and led to a dose-dependent reduction in PI3K/AKT pathway activity and improved the immune dysregulation with normalization of circulating transitional and naïve B cells and reduction in PD-1+CD4+ and senescent CD57+CD8+ T cells. Elevated serum IgM and other biomarkers including IFNg, TNF, CXCL13 and CXCL10 normalized or decreased with leniolisib. Cytopenias and lymphoproliferation improved in all patients with index lymph node sizes and spleen volumes reduced by 39% and 40%, respectively. Here we report the long term follow up safety and efficacy data in all six patients (Table 1) who have continued treatment with leniolisib in an extension study at 70 mg b.i.d (ClinicalTrials.gov number NCT02859727). These patients have been treated for up to 949 days (as of July 20th 2018). Three of them were lymphoma survivors. Three patients were treated with rapamycin prior to starting leniolisib. No patient in the 12-week clinical trial or in the long term extension study has experienced any significant adverse events. Notably, side effects prevalent with mTOR or other PI3K inhibitors such as diarrhea/colitis, skin rashes, susceptibility to infections or liver enzyme elevation were absent. Three patients have stopped immunoglobulin supplementation as a reflection of the normalization of their B cell function. Cytopenias, including anemia, thrombocyopenia, neutropenia and lymphopenia have continued to improve. (Figure 1: Showing representative improvement of laboratory data including normalization of IgM for patient 002, following 18 months of treatment with leniolisib; Figure2: Showing improvement of lymphoproliferation in CT scans from 2016 and 2018 for Patient 003. This patient stopped leniolisib for 15 months from October 2016 until January 2018 leading to worsening lymphoproliferation that improved promptly on resumption of therapy). Available data on longterm safety, effects on lymphoproliferation and immune dysregulation in the ongoing leniolisib extension study will be shared during the meeting. The results support safe and efficacious long term inhibition of PI3Kδ protein as a new targeted therapeutic approach in APDS and other disorders of nonmalignant lymphopoliferation associated with hyperactive PI3Kinase pathway. Disclosures Rao: novartis: Research Funding. Dalm:Novartis: Research Funding. Sediva:Novartis: Research Funding. van Hagen:Novartis: Research Funding. Cabanski:Novartis: Employment. Valentin:Novartis: Employment. de Buck:Novartis: Employment. Kalis:Novartis: Employment. Hasselberg:Novartis: Employment. Burkhart:Novartis: Employment. Kucher:Novartis: Employment. Sloth:Novartis: Employment. Uzel:Novartis: Research Funding.

Shared Pathogenetic Features Between Common Variable Immunodeficiency and Sjögren’s Syndrome: Clues for a Personalized Medicine

“…On the other hand, leniolisib (CDZ173), a potent and selective oral inhibitor of PI3Kdelta ( 128 ), has been successfully used in a series of patients with APDS, in which PI3Kdelta gain-of-function mutation results in lymphoproliferation of the MALT, T-cell senescence and immunodeficiency. Leniolisib normalized B cells in APDS, and improved lymphoproliferation ( 129 ). A phase II clinical trial [NCT02775916] assessing the safety, pharmacokinetics, and preliminary efficacy of leniolisib in SS has been completed in January 2021, and preliminary data were presented in 2018 ( 130 ).…”

Design and Optimization of Thienopyrimidine Derivatives as Potent and Selective PI3Kδ Inhibitors for the Treatment of B-Cell Malignancies

“…Another two PI3Kδ inhibitors nemiralisib and GSK-2292767, developed as an inhaled form, have been in clinical trials for the treatment of asthma and chronic obstructive pulmonary disease (COPD) . Moreover, CDZ173, a structurally distinct PI3Kδ inhibitor, is within phase II/III trials to assess its safety and efficacy in patients with APDS/p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) …”

“…30 Moreover, CDZ173, a structurally distinct PI3Kδ inhibitor, is within phase II/III trials to assess its safety and efficacy in patients with APDS/p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI). 31 Given significant advancement for PI3Kδ inhibitors in the field of drug discovery, targeting PI3Kδ by structurally novel scaffolds bearing optimized potency and selectivity is still needed for exploration of therapeutics with improved safety and efficacy profiles. 32 In this work, we chose the clinical candidate CDZ173 as a structural template that features a core of 5,6,7,8-tetrahydropyrido [4,3-d]-pyrimidine (THPP).…”